Boehringer Ingelheim announced the launch of the Phase III RESIST clinical trial program designed to further study the efficacy and safety of tipranavir for use in combination therapy for HIV-1 infection. The RESIST 1 & 2 trials and accompanying companion studies will evaluate triple class-experienced patients1 in more than 280 clinical trial sites worldwide. Tipranavir is the first non-peptidic protease inhibitor (NPPI) in development for the treatment of HIV-1 infection. It will be Boehringer Ingelheim`s second antiretroviral drug following Viramune (nevirapine), which is a non-nucleoside reverse transcriptase inhibitor.
Resistance to currently available anti-HIV drugs is an increasingly prevalent concern for highly treatment-experienced HIV-positive patients worldwide, creating an urgent need for new treatments that are effective against multi-drug resistant virus. Up to 14 per cent of recently infected patients have been reported to be infected with a strain of virus that has drug resistance mutations or that has reduced susceptibility to a particular drug (resulting in reduced drug effectiveness) 2, 3, 4 . Based on available clinical and in vitro data, tipranavir shows activity against multi-drug resistant HIV virus, offering hope for patients with multi-drug resistant virus.
"This is an important milestone in the development of tipranavir," said Dr Andreas Barner, member of the board of managing directors of Boehringer Ingelheim. "We have designed a clinically relevant Phase III trial program that includes resistance testing for all patients, allows the use of other expanded access HIV/AIDS therapies, and provides access to a significant number of triple class-experienced patients worldwide. It`s the largest trial program ever conducted in this patient population, recruiting over 1,500 patients in total."
The Phase III RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug ReSistant Patients with Tipranavir) clinical trial program has been designed to study the safety and efficacy of tipranavir (boosted with low-dose ritonavir) versus a low-dose ritonavir-boosted comparator protease inhibitor (PI) that is chosen by the patient`s physician on the basis of treatment history and baseline resistance testing. Study participants will all be highly treatment-experienced HIV-positive adults. Phase III of clinical development is the final stage of testing before a drug is submitted to worldwide regulatory authorities for review and consideration for marketing approval. The RESIST Program consists of two Phase III pivotal trials (RESIST 1 and RESIST 2) and two companion trials (study 1182.51 and RESIST 3) available at some sites for even more advanced patients.
"Initial studies have demonstrated that tipranavir is among the most promising anti-HIV drugs in development - particularly for treatment-experienced patients unable to construct a viable regimen with currently available antiretrovirals. I look forward to seeing the outcome of these important Phase III trials," said Kathleen Squires, MD, Associate Professor of Medicine at the Keck School of Medicine of the University of Southern California, and an investigator in the RESIST program.
RESIST 1 will enroll more than 500 patients in the USA, Canada and Australia. RESIST 2 will enroll more than 800 patients in Europe and in South America. The clinical endpoint for the RESIST 1 study is at 24 weeks and for the RESIST 2 study the endpoints are at 16 and 24 weeks. All participants will receive resistance testing at baseline to determine the optimal drugs to combine with tipranavir, as each patient will receive an individualized background treatment regimen. The choice of comparator PI and background regimen is up to the investigator.
Highly treatment experienced HIV-positive patients interested in enrolling in one of the RESIST trials should contact their local HIV/AIDS healthcare provider to find a local site that is participating in the trial.
Additional companion studies will also be available at some participating pivotal study sites for patients who do not qualify for the pivotal trial protocol. Boehringer Ingelheim will also study tipranavir in treatment-naïve adult patients and conduct trials in children. The dose for tipranavir that will be studied in the Phase III clinical program is 500 mg of tipranavir taken with 200 mg of ritonavir (to boost tipranavir drug levels in the body) twice daily.
Tipranavir has a non-peptidic chemical structure, which allows it to bind more flexibly to the active site of the HIV protease. This flexibility appears to explain why the resistance profile of tipranavir is different from available peptidic PIs. While the exact resistance profile of tipranavir is still being defined, initial clinical and in vitro data indicate it is superior to currently available protease inhibitors. Results from Phase II clinical studies have shown that reduction in the susceptibility of HIV to tipranavir was very infrequent and was associated with at least 16 protease inhibitor mutations at baseline.
The HIV-1 virus acquires HIV drug resistance after sub-optimal exposure to antiretroviral therapy, which becomes more of an issue the longer patients are receiving treatment. Drug resistance may render drugs less effective, or even ineffective, thus significantly limiting treatment options for people with HIV/AIDS. Resistance generally occurs as a result of changes - or mutations - in HIV`s genetic code.